Charurut Somboonwit

Editorial NeuroAIDS review

NeuroAIDS is a disease that incorporates both infectious and degenerative pathophysiologic pathways. It has a known cause, has several animal models, and is under investigation and treatment using multiple avenues, in vivo and in vitro [1–7]. Select highlights from the spectrum of NeuroAIDS research predominantly related to human immunodeficiency virus-1 clade B (HIV-1B) are reviewed below.

Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection

BACKGROUND Elite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV. METHODS For adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts ≥350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia. All-cause and diagnostic category-specific hospitalization rates were compared between groups using negative binomial regression. RESULTS We identified 149 elite controllers (0.4%) among 34 354 persons in care. Unadjusted hospitalization rates among the medical control, elite control, low-viremia, and high-viremia groups were 10.5, 23.3, 12.6, and 16.9 per 100 person-years, respectively. After adjustment for demographic and clinical factors, elite control was associated with higher rates of all-cause (adjusted incidence rate ratio, 1.77 [95% confidence interval, 1.21-2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28]) hospitalization than was medical control. Non-AIDS-defining infections were the most common reason for admission overall (24.1% of hospitalizations) but were rare among elite controllers (2.7%), in whom cardiovascular hospitalizations were most common (31.1%). CONCLUSIONS Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor.

Elite Controllers are Hospitalized More Often than Persons with Medically Controlled HIV

BACKGROUND Elite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV. METHODS For adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts ≥350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia. All-cause and diagnostic category-specific hospitalization rates were compared between groups using negative binomial regression. RESULTS We identified 149 elite controllers (0.4%) among 34 354 persons in care. Unadjusted hospitalization rates among the medical control, elite control, low-viremia, and high-viremia groups were 10.5, 23.3, 12.6, and 16.9 per 100 person-years, respectively. After adjustment for demographic and clinical factors, elite control was associated with higher rates of all-cause (adjusted incidence rate ratio, 1.77 [95% confidence interval, 1.21-2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28]) hospitalization than was medical control. Non-AIDS-defining infections were the most common reason for admission overall (24.1% of hospitalizations) but were rare among elite controllers (2.7%), in whom cardiovascular hospitalizations were most common (31.1%). CONCLUSIONS Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor.

Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations.

Background:There are contradictory reports regarding the effects of protease inhibitors on the ECG measures of QT and PR interval durations. The effect of interrupting use of protease inhibitors on QT and PR progression is also unknown. Methods:This analysis included 3719 participants from the Strategies for Management of Antiretroviral Therapy (SMART) study, of whom 1879 were randomized to receive intermittent antiretroviral therapy (ART) (drug conservation group), whereas the rest received these drugs continuously (viral suppression group). Linear regression analysis was used to compare four ritonavir-boosted protease inhibitor (protease inhibitor/r) regimens [saquinavir (SQV/r), lopinavir (LPV/r), atazanavir (ATV/r), and other protease inhibitor/r], and nonboosted protease inhibitor regimens with nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens for Bazetts (QTcB) and Fredericias (QTcF) heart rate corrected QT and PR. Changes in QTcB, QTcF, and PR after 12 and 24 months of randomization were compared in the drug conservation group and viral suppression group. Results:Average levels of QTcB, QTcF, and PR duration at entry were 415, 406, and 158 ms. At study entry, 49% of participants were taking an NNRTI (no protease inhibitor)-based regimen and 31% were prescribed a boosted protease inhibitor, the most common being LPV/r. After adjustment for baseline factors, QTcB and QTcF levels did not vary by boosted protease inhibitor group (P = 0.26 and P = 0.34, respectively). For those given any of the boosted protease inhibitors, QTcB was 1.5 ms lower than the NNRTI group (P = 0.04). Both boosted and nonboosted protease inhibitor-containing regimens were significantly associated (P < 0.01 for each) with longer PR intervals compared to the NNRTI group. After adjustment, the difference between boosted protease inhibitors and the NNRTI group was 5.11 ms (P < 0.01); for nonboosted protease inhibitors, this difference was 3.00 ms (P < 0.01). Following ART interruption, PR duration declined for both the boosted and nonboosted protease inhibitor groups and compared to the viral suppression group, significant changes in PR interval were observed 24 months after ART interruption of boosted protease inhibitors (P < 0.01). Conclusion:Different protease inhibitor-based regimens have a similar, minimal effect on QT compared to NNRTI-based regimens. All protease inhibitor-based regimens (boosted and nonboosted) were associated with prolongation of PR, and interruption of protease inhibitor regimens reduced the prolonged PR duration. Further research is needed to confirm the findings of this study and assess the clinical relevance of the differences.

The HIV Care Continuum: Changes over Time in Retention in Care and Viral Suppression

Background The HIV care continuum (diagnosis, linkage to care, retention in care, receipt of antiretroviral therapy (ART), viral suppression) has been used to identify opportunities for improving the delivery of HIV care. Continuum steps are typically calculated in a conditional manner, with the number of persons completing the prior step serving as the base population for the next step. This approach may underestimate the prevalence of viral suppression by excluding patients who are suppressed but do not meet standard definitions of retention in care. Understanding how retention in care and viral suppression interact and change over time may improve our ability to intervene on these steps in the continuum. Methods We followed 17,140 patients at 11 U.S. HIV clinics between 2010-2012. For each calendar year, patients were classified into one of five categories: (1) retained/suppressed, (2) retained/not-suppressed, (3) not-retained/suppressed, (4) not-retained/not-suppressed, and (5) lost to follow-up (for calendar years 2011 and 2012 only). Retained individuals were those completing ≥2 HIV medical visits separated by ≥90 days in the year. Persons not retained completed ≥1 HIV medical visit during the year, but did not meet the retention definition. Persons lost to follow-up had no HIV medical visits in the year. HIV viral suppression was defined as HIV-1 RNA ≤200 copies/mL at the last measure in the year. Multinomial logistic regression was used to determine the probability of patients’ transitioning between retention/suppression categories from 2010 to 2011 and 2010 to 2012, adjusting for age, sex, race/ethnicity, HIV risk factor, insurance status, CD4 count, and use of ART. Results Overall, 65.8% of patients were retained/suppressed, 17.4% retained/not-suppressed, 10.0% not-retained/suppressed, and 6.8% not-retained/not-suppressed in 2010. 59.5% of patients maintained the same status in 2011 (kappa=0.458) and 53.3% maintained the same status in 2012 (kappa=0.437). Conclusions Not counting patients not-retained/suppressed as virally suppressed, as is commonly done in the HIV care continuum, underestimated the proportion suppressed by 13%. Applying the care continuum in a longitudinal manner will enhance its utility.

The Influenza Pandemic of 2009

Influenza is a moving target, which evolves in unexpected directions and is recurrent annually. The 2009 influenza A/H1N1 pandemic virus was unlike the 2009 seasonal virus strains and originated in pigs prior to infecting humans. Three strains of viruses gave rise to the pandemic virus by antigenic shift, reassortment, and recombination, which occurred in pigs as ‘mixing vessels’. The three strains of viruses had originally been derived from birds, pigs, and humans. The influenza hemagglutinin (HA) and neuraminidase (NA) external proteins are used to categorize and group influenza viruses. The internal proteins (PB1, PB1-F2, PB2, PA, NP, M, and NS) are involved in the pathogenesis of influenza infection. A major difference between the 1918 and 2009 pandemic viruses is the lack of the pathogenic protein PB1-F2 in the 2009 pandemic strains, which was present in the more virulent 1918 pandemic strains. We provide an overview of influenza infection since 1847 and the advent of influenza vaccination since 1944. Vaccines and chemotherapy help reduce the spread of influenza, reduce morbidity and mortality, and are utilized by the global rapid-response organizations associated with the WHO. Immediate identification of impending epidemic and pandemic strains, as well as sustained vigilance and collaboration, demonstrate continued success in combating influenza.

Platelet count kinetics following interruption of antiretroviral treatment

Objectives:To investigate the mechanisms of platelet kinetics in the Strategies for Management of Antiretroviral Therapy (SMART) study that demonstrated excess mortality with CD4 guided episodic antiretroviral therapy (ART) drug conservation compared with continuous treatment viral suppression. Follow-up analyses of stored plasma samples demonstrated increased activation of both inflammatory and coagulation pathways after stopping ART. Design:SMART patients from sites that determined platelets routinely. Methods:Platelet counts were retrospectively collected from 2206 patients from visits at study entry, and during follow-up. D-dimer levels were measured at study entry, month 1, and 2. Results:Platelet levels decreased in the drug conservation group following randomization, but remained stable in the viral suppression group [median (IQR) decline from study entry to month 4: −24 000/&mgr;l (−54 000 to 4000) vs. 3000 (−22 000 to 24 000), respectively, P < 0.0001)] and the rate of developing thrombocytopenia (<100 000/&mgr;l) was significantly higher in the drug conservation vs. the viral suppression arm (unadjusted drug conservation/viral suppression [HR (95%CI) = 1.8 (1.2–2.7)]. The decline in platelet count among drug conservation participants on fully suppressive ART correlated with the rise in D-dimer from study entry to either month 1 or 2 (r = −0.41; P = 0.02). Among drug conservation participants who resumed ART 74% recovered to their study entry platelet levels. Conclusion:Interrupting ART increases the risk of thrombocytopenia, but reinitiation of ART typically reverses it. Factors contributing to declines in platelets after interrupting ART may include activation of coagulation pathways or HIV-1 replication itself. The contribution of platelets in HIV-related procoagulant activity requires further study.

Kidney disease in antiretroviral‐naïve HIV‐positive adults with high CD4 counts: prevalence and predictors of kidney disease at enrolment in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial

HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap.

Kidney disease in antiretroviral-naïve HIV-positive adults with high CD4 counts

HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap.

Healthcare Coverage for HIV Provider Visits Before and After Implementation of the Affordable Care Act

BACKGROUND Before implementation of the Patient Protection and Affordable Care Act (ACA) in 2014, 100 000 persons living with human immunodeficiency virus (HIV) (PLWH) lacked healthcare coverage and relied on a safety net of Ryan White HIV/AIDS Program support, local charities, or uncompensated care (RWHAP/Uncomp) to cover visits to HIV providers. We compared HIV provider coverage before (2011-2013) versus after (first half of 2014) ACA implementation among a total of 28 374 PLWH followed up in 4 sites in Medicaid expansion states (California, Oregon, and Maryland), 4 in a state (New York) that expanded Medicaid in 2001, and 2 in nonexpansion states (Texas and Florida). METHODS Multivariate multinomial logistic models were used to assess changes in RWHAP/Uncomp, Medicaid, and private insurance coverage, using Medicare as a referent. RESULTS In expansion state sites, RWHAP/Uncomp coverage decreased (unadjusted, 28% before and 13% after ACA; adjusted relative risk ratio [ARRR], 0.44; 95% confidence interval [CI], .40-.48). Medicaid coverage increased (23% and 38%; ARRR, 1.82; 95% CI, 1.70-1.94), and private coverage was unchanged (21% and 19%; 0.96; .89-1.03). In New York sites, both RWHAP/Uncomp (20% and 19%) and Medicaid (50% and 50%) coverage were unchanged, while private coverage decreased (13% and 12%; ARRR, 0.86; 95% CI, .80-.92). In nonexpansion state sites, RWHAP/Uncomp (57% and 52%) and Medicaid (18% and 18%) coverage were unchanged, while private coverage increased (4% and 7%; ARRR, 1.79; 95% CI, 1.62-1.99). CONCLUSIONS In expansion state sites, half of PLWH relying on RWHAP/Uncomp coverage shifted to Medicaid, while in New York and nonexpansion state sites, reliance on RWHAP/Uncomp remained constant. In the first half of 2014, the ACA did not eliminate the need for RWHAP safety net provider visit coverage.